Monoamine reuptake inhibitors increase the extracellular levels of monoamine neurotransmitter, i.e. norepinephrine, serotonin and dopamine, causing a cascade of intracellular neurochemical changes that eventually lead to the desired therapeutic CNS effect (Bymaster et al., Neuropsychopharmacology 27:699-711. (2002); Richelson, J. Clin. Psychiatry. 64:5-12. (2003)). These reuptake inhibitors have potential uses as medications in a wide variety of neuropsychiatric disorders ranging from anxiety and depression to eating disorders and drug or alcohol addiction. One potential use is as antidepressants. Selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine (Prozac®) and sertraline (Zoloft®), and serotonin and norepinephrine reuptake inhibitors (SNRIs), e.g. venlafaxine (Effexor®), and duloxetine (Cymbalta®), have been widely applied to treat depression and anxiety disorders. There is increasing evidence from both preclinical and clinical studies showing that simultaneous blockage of reuptake of serotonin, norepinephrine, and dopamine may achieve better desired effects than using single or dual reuptake inhibitors. (Skolnick, J. Clin. Psychiatry. 63 (suppl. 2): 19-23. (2002)) In this context, compounds having “broad spectrum” inhibition of monoamine reuptake may yield a more rapid onset and/or higher efficacy of antidepressant activity than currently available antidepressants, including agents that inhibit single or dual reuptake of serotonin and/or norepinephrine (Skolnick et al., Eur. J. Pharmacol. 461:99 (2003); Skolnick, P., Popik, P., Janowsky, A., Beer, B., and Lippa, A. S.: “Broad spectrum” antidepressants: Is more better for the treatment of depression? Life Sci., 73: 3175-3179, 2003).
In view of the limited availability and understanding of currently-known “broad spectrum antidepressants”, there remains a compelling need in the art to identify additional drugs having multiple reuptake inhibitory potential for inhibiting reuptake of multiple biogenic amines linked to disorders of the central nervous system (CNS), including neuropsychiatric disorders, such as depression and anxiety.
It is therefore an object of the present invention to provide novel compounds having activity to inhibit reuptake of one or multiple biogenic amines linked to CNS disorders, and to provide related compositions, and methods for treating and managing CNS disorders, including depression and anxiety. 